DESCRIPTION: This is a revised proposal designed to investigate the genetic and cellular basis of a recently identified X-linked cerebellar ataxia in English pointer dogs. Affected males hemizygous for X-linked canine ataxia (XCA) show progressive dysmetria and downbeat nystagmus, which is associated with the loss of cerebellar Purkinje cells. XCA thus represents a new model for hereditary cerebellar ataxia in humans. The genetic-analysis components of this proposal include plans to establish a breeding colony of dogs segregating XCA; to confirm the tight linkage of XCA to the androgen-receptor gene on the canine X chromosome; to determine whether there are any defects in the androgen-receptor gene itself that can be correlated with the mutant phenotype; and to identify polymorphisms in flanking X-chromosome loci for the purpose of improving and validating carrier detection. In parallel with these genetic studies, the investigator proposes to characterize the clinical course of the disease in symptomatic affected dogs (usually greater than six months old) and to identify any cerebellar defects associated with their phenotype. Likewise, he proposes to determine the nature of the earliest detectable cerebellar lesions in presymptomatic males that are known to carry the mutant gene by virtue of the genotypes of the androgen- receptor gene and the X-chromosome loci flanking the XCA locus. If the proposed studies funded by the AREA grant indicate that XCA is a good model for more general types of neurodegenerative diseases, a more extensive research program will be proposed that will address the identification of the aberrant gene product involved in the disorder, as well as the analysis of aberrant neurochemical and cellular changes involved in the etiology of the disease. Thus, these studies could then form the basis of a more extensive analysis on possible therapeutic strategies that would have implications for both veterinary and human medicine.